Synthesis and cytotoxicity studies of new analogues of polyamines.
In order to regulate simultaneously the biosynthesis and the transport of natural polyamines, the synthesis of a series of N-methylated analogues of N,N1-Bis(benzyl)-alkanediamines (propanediamine and butanediamine) was achieved and the cytotoxicity of these compounds on the P388D1 cell line was determined. Experiments were conducted in a growth culture medium 20 microM of 2-mercaptoethanol or 0.1 mM of aminoguanidine. Their cytotoxic effects were compared to those obtained under the same conditions with natural polyamines known as toxic compounds at high concentrations. The IC50 of each compound was found very similar for all experimental conditions (IC50 approximately 150 microM) at the opposite of spermidine and spermine which were less toxic (IC50 > 500 microM) when cells were grown in the presence of aminoguanidine (a specific inhibitor of fetal calf serum's PAO). The DL-difluoromethylornithine (DFMO) and MDL 72527DA, two well known inhibitors of ornithine decarboxylase (ODC) and Polyamine Oxidase (PAO) respectively, had no toxicity on the P388D1 cells compared to our compounds. Our most toxic compound was N1,N4-Bis(benzyl)-N1,N4-bis(methyl)-1,4-butanediamine (6) with an IC50 of 127 +/- 3 microM (in culture medium alone). The synthesis of the beta-aminothioether derivative of N-benzylputrescine (11) and the beta-aminothiol derivative of N-benzylspermidine (13) were also related. The Compound 11 was tested against the P388D1 cells, and did not show any cytotoxic effect. The N-methyl derivatives should give the advantage to be used at low concentrations than those used to test the DFMO.
Badolo
L
L
Laboratoire de Chimie Bioanalytique de Toxicologie et de Chimie Physique Appliquée, Université Libre de Bruxelles, Belgique.
Gelbcke
M
M
Dubois
J
J
Hanocq
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D007941:Leukemia P388 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity
D000970:Antineoplastic Agents; D011073:Polyamines